ABSTRACTS HIV-1 infection is a worldwide problem for vaccine development. More than 25 million people are infected with in sub-Saharan Africa, a geographic area that poses unique challenges for vaccine development. The bulk of earlier studies of immunopathogenesis have been performed in Europe and the Americas. However, sub-Saharan Africa is the epicenter of the HIV-1 epidemic, and host and viral genetics vary significantly between geographic regions. The MHC alleles of African human populations vary from those of the West, and there is a diversity of viral sequences that are distinct from the Clade B strains dominating Europe and the Americas. Furthermore, the environment in sub-Saharan Africa is vastly different; in particular there are many parasitic infections that are immunomodulatory and likely affect the host response to HIV-1 infection and vaccines. Because cellular immunity plays an important protective role in HIV-1 pathogenesis, recent vaccine efforts have focused heavily on generating antiviral CD8+ T lymphocyte (CTL) responses to attenuate infection (if not provide full protection). However, the recent decision by Merck to abandon its Phase II clinical trial (STEP) due to lack of efficacy underscores the importance of better understanding mechanisms in the immunopathogenesis of HIV-1 infection and factors affecting the antiviral efficiency of CTL . Uganda is a country in which HIV-1 has spread rapidly, but which has been extraordinary in its response to the AIDS epidemic. This was the first country in Africa to test HIV-1 vaccines, and Uganda has taken leadership in introducing antiretroviral (ARV) programs to its affected population. Over the prior funding periods of this R01, we have capitalized on the dedication of this country to HIV-1 research, and established the infrastructure to study immunopathogenesis there. Uganda offers a unique opportunity to address relevant issues specific to sub-Saharan Africa, in a setting where applications of the findings may be immediate. This renewal project will pursue questions that are relevant for vaccine and immunotherapeutic interventions in sub-Saharan Africa, employing our research operation in Uganda as a platform. We will explore the influences of host and viral genetics, and immunomodulatory effects of concurrent helminth infections on HIV-1 immunopathogenesis. Our proposed three aims are: 1) To determine the targeting and cross-clade antiviral activity of HIV-1-specific CTL in Ugandan genetic contexts. 2) To examine CTL epitope variation and Nef-mediated HIV-1 immune evasion in Ugandan genetic contexts. 3) To evaluate whether endemic co-infections may modulate of HIV-1 immununopathogenesis in Uganda, using Schistosoma mansoni as a model infection.